Despite the advance of antibiotics, sepsis remains a major challenge to human health as both survival and incidence of severe sepsis have been largely unchanged in the last two decades. It is therefore important to develop new therapeutic approaches. We have recently reported that bacterial sialidases may serve as therapeutic targets for polybacterial sepsis. However, since the majority of bacteria that cause sepsis do not encode sialidases, targeting bacterial sialidases alone would be insufficient for therapy of sepsis. In order to expand the original concept to infections by microbes that do not produce sialidases, we hereby hypothesize that host sialidases can also be targeted for the treatment of sepsis. In support of this notion, we observed that a novel sialidase inhibitor 2-deoxy-2,3-dehydro-N-glycolylneuraminic acid (Neu5Gc2en) conferred 100% protection against lethal endotoxic shock. Since endotoxin does not contain microbial sialidases, the inhibitor has to target the host sialidase(s). Furthermore, using mice with a targeted mutation of Neu1 gene among the hematopoietic cells, we demonstrated a critical role for NEU1 in both severity of endotoxic shock and in therapeutic response to Neu5Gc2en. These results demonstrate that NEU1 is a potential therapeutic target for endotoxic shock, which contributes to pathogenesis of sepsis and remains largely unresponsive to current therapy. Based on these exciting observations, we will compare therapeutic effect of a series of newly synthesized sialidase inhibitors for their activity and selectivity for NEU1. The goal is to identify a lead compound tha is effective in treating endotoxic shock with minimal toxicity.